The incidence of melanoma has risen steadily over the last 30 years. Indeed, the vast majority of skin cancer deaths are due to melanoma, which is very difficult to treat once disease becomes metastatic. Inhibitors of oncogenic BRAF (BRAFi), vemurafenib and dabrafenib, and the MEK inhibitor (MEKi) trametinib improve response rate, progression free survival (PFS), and overall survival compared to chemotherapy in patients with metastatic, BRAF-mutant melanoma, about 50% of cases. Further, three randomized phase 3 trials have now demonstrated superior RR, PFS, and OS of combination BRAFi/MEKi compared to single agent BRAFi without a dramatic increase in toxicity. In fact, classic BRAFi toxicity such as rash, hand-foot-syndrome, and second malignancies are reduced with the addition of a MEKi. Based on this data, dabrafenib and trametinib (DT) has become a new standard of care. Still, most patients treated with BRAFi and MEKi experience disease progression and die from their disease. One potential way to improve the upfront effectiveness of BRAF- directed therapy is to target apoptosis. Oncogenic BRAF suppresses cell death through a number of mechanisms, but most importantly, it down modulates the pro-apoptotic BCL-2 homology domain 3 (BH3)-only protein BIM. BRAFi and MEKi increased levels of BIM in melanoma cell lines in vitro and in vivo, which is responsible for apoptosis induction seen in this setting. In patients, we demonstrated that treatment with either vemurafenib or DT is associated with a significant increase in BIM protein and mRNA levels, as well as increased anti-apoptotic BCL-2 family members BCL-xL and BCL-w. Navitoclax (ABT-263) is a small molecule inhibitor that functions as a BH3-mimetic which specifically binds and inactivates anti-apoptotic BCL-2, BCL-xL, and BCL-w, thereby enhancing the proapoptotic activity of BIM. Preclinical data suggest that navitoclax combined with BRAFi and/or MEKi profoundly decreases cell viability, and increases tumor regression and apoptosis. Based on these data, we opened a CTEP-sponsored phase I/II study of navitoclax in combination with DT (DTN). In this proposal, we aim to identify the maximally tolerated dose of DTN (phase I portion, open to patients with BRAF-mutant solid tumors), then evaluate the efficacy of DTN compared with DT in patients with BRAF-mutant, BRAFi-nave metastatic melanoma (phase II). We will explore biomarkers that predict outcome to DTN, and determine pharmacodynamic effects of DTN and DT on pre- and on-treatment biopsies. We will simultaneously use xenograft, syngeneic and genetically engineered mouse models of melanoma to study the efficacy of alternate dosing strategies. Finally, we will employ advanced sequencing analyses of treatment resistant human and mouse tumors to identify candidate resistance genes for further study in preclinical models, to determine the mechanisms for development of resistance. This work will thus determine the ideal strategy for implementing a new therapeutic, precision medicine approach to improve clinical outcomes of patients with BRAF mutant melanoma and potentially, other BRAF mutant solid tumors.